Abstract
CD2-like receptor activating cytotoxic cells (CRACC) is known as a critical activating receptor of natural killer (NK) cells. We have previously reported that NK cells contribute to Poly I:C/D-galactosamine (D-GalN)-induced fulminant hepatitis. Since natural killer group 2, member D (NKG2D) is considered critical but not the only activating receptor for NK cells, we investigated the role of CRACC in this model. We found that CRACC was abundant on hepatic NK cells but with low expression levels on Kupffer cells under normal conditions. Expression of CRACC on NK cells and Kupffer cells was remarkably upregulated after poly I:C injection. Hepatic CRACC mRNA levels were also upregulated in Poly I:C/D-GalN-treated mice, and correlated positively with the serum alanine aminotransferase (ALT) levels. CRACC expression on Kupffer cells was specifically silenced by nano-particle encapsulated siRNA in vivo, which significantly reduced Poly I:C/D-GalN-induced liver injury. In co-culture experiments, it was further verified that silencing CRACC expression or blockade of CRACC activation by mAb reduced the production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Collectively, our findings suggest that CRACC-CRACC interaction between NK cells and resident Kupffer cells contributes to Poly I:C/D-GalN-induced fulminant hepatitis.
Highlights
The liver is the largest digestive glands and the critical portal to the microorganisms derived from digestive tract
Our previous studies demonstrated that Poly I:C/D-GalNinduced liver injury was mediated by tumor necrosis factor (TNF)-α and IFN-γ, which were produced during the natural killer (NK)-Kupffer cell interaction, we focused on the effect of CD2-like receptor activating cytotoxic cells (CRACC) to the TNF-α and IFN-γ production
This study has demonstrated that CRACC-CRACC interaction between hepatic NK cells and Kupffer cells plays an important role in promoting the Poly I:C/D-GalN induced liver injury
Summary
The liver is the largest digestive glands and the critical portal to the microorganisms derived from digestive tract. Emerging evidence suggests that the liver is considered as an innate immunity associated organ, because liver immune cells are enriched in innate immune cells including NK cells, NKT cells, Kupffer cells and γδT cells [1], compared with peripheral blood and other organs The immunomodulation among these cells is critical to the orchestration of immune reaction. Our previous study has established an acute liver injury model induced by poly I:C and D-galactosamine (D-GalN) [6]. In this model, activation of natural killer group 2, member D (NKG2D) by recognizing retinoic acid early inducible-1 (Rae1) on Kupffer cells induces NK cell-mediated fulminant hepatitis. It is reasonable to speculate that CRACC is an activating receptor on NK cells involved in this Poly I:C/D-GalN induced hepatitis model. We found Poly I:C stimulation markedly elevated the expression of CRACC on both Kupffer cells and NK cells; and CRACC interaction between NK cells and Kupffer cells contributed to the Poly I:C/D-GalN induced liver injury by increasing the production of IFN-γ and TNF-α
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